Legionella pneumophila is an important causative agent of severe pneumonia in humans. The human alveolar epithelium is an effective barrier for inhaled microorganisms and actively participates in the initiation of innate host defense. Although secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) is essential for the elimination of invading Legionella spp., mechanisms of Legionella pneumophila-induced release of this cytokine are widely unknown.

In this study, we have demonstrated a toll-like receptor (TLR)2- and TLR5-dependent release of GM-CSF in L. pneumophila-infected human alveolar epithelial cells. GM-CSF secretion was not dependent on the bacteria type II or type IV secretion system. Furthermore, an increase in protein kinase C (PKC) activity, particularly PKCα and PKCϵ, was noted. Blocking of PKCα and PKCϵ activity or expression, but not of PKCβ, PKCδ, PKCη, PKCθ, and PKCζ, significantly reduced the synthesis of GM-CSF in infected cells. While PKCα was critical for the initiation of a nuclear factor-κB-mediated GM-CSF expression, PKCϵ regulated GM-CSF production via activator protein 1.

Thus, differential regulation of GM-CSF, production by PKC isoforms, contributes to the host response in Legionnaires' disease.